A Multi-Centre, Tolerability Study of a Cannabidiol-enriched Cannabis Herbal Extract for Chronic Headaches in Adolescents: the CAN-CHA Protocol

Introduction Cannabis products have been used in the management of headaches in adults and may play a role in pediatric chronic pain. Canadian pediatricians report increasing use of cannabis for the management of chronic headaches, despite no well-controlled studies to inform its dosing, safety, and effectiveness. The aim of our clinical trial is to determine the dosing and safety of a Cannabidiol (CBD)-enriched Cannabis Herbal Extract (CHE) for the treatment of chronic headaches in adolescents. Methods and analysis Youth, parents and an expert steering committee co-designed this tolerability study. Twenty adolescents (aged 14 to 17 years), with a chronic migraine diagnosis for more than 6 months that has not responded to other therapies, will be enrolled into an open label, dose escalation study across three Canadian sites. Study participants will receive escalating doses of a CBD-enriched CHE (MPL-001 with a THC:CBD of 1:25), starting at 0.2-0.4 mg/kg of CBD per day escalating monthly up to 0.8-1.0 mg/kg of CBD per day. The primary objective of this study is to determine the safety and tolerability of CBD-enriched CHE in adolescents with chronic migraine. Secondary objectives of this study will inform the development of subsequent randomized controlled trials and include investigating the relationship between the dose escalation and change in the frequency of headache, impact and intensity of pain, changes in sleep, mood, function, and quality of life. Exploratory outcomes include investigating steady-state trough plasma levels of bioactive cannabinoids and investigating how pharmacogenetic profiles affect cannabinoid metabolism among adolescents receiving CBD-enriched CHE. Discussion This protocol was co-designed with youth and describes a tolerability clinical trial of CBD-enriched CHE in adolescents with chronic headaches that have not responded to conventional therapies. This study is the first clinical trial on cannabis products in adolescents with chronic headaches and will inform the development of future comparative effectiveness clinical trials. Trial registration: CAN-CHA trial is registered with ClinicalTrials.gov with a number of register [NCT05337033][1]. ### Competing Interest Statement I have read the journal's policy and the authors of this manuscript have the following competing interests: LEK is the Scientific Director for The Canadian Collaborative for Childhood Cannabinoid Therapeutics (C4T) academic research team. She holds funding from the Canadian Institutes of Health Research, Canadian Cancer Society, Research Manitoba, the Sick Kids Foundation, the Children?s Hospital Research Institute of Manitoba, the University of Manitoba and a Mitacs Accelerate award in partnership with Canopy Growth. Dr. Kelly is also a member of the Scientific Advisory Board for Health Products Containing Cannabis at Health Canada and a member of the Board of Directors of the Canadian Consortium for the Investigation of Cannabinoids (CCIC). RJH is a clinical lead for both the Cannabinoid Research Initiative of Saskatchewan and C4T. He is developing a research protocol in which cannabis products will be supplied in kind by JMCC Corporation. He is a co-chair of the Scientific Advisory Committee for Health Products Containing Cannabis at Health Canada. KEB's time is supported by a fellowship from the Canadian Child Health Clinician Scientist Program, and she currently holds unrelated funding from the Society of Pediatric Psychology, BC Children's Hospital Research Institute, Canadian Institutes of Health Research, ZonMw: The Netherlands Organization for Health Research and Development, and the CHILD-BRIGHT Network. ECL has received speaking honoraria from Spectrum Therapeutics, Biome Grow, MedReleaf and Miravo Healthcare. He holds a non-salaried position as the Chief Medical Advisor for the JMCC Group. He is the Vice President of Neurology Services for Numinus, a psychedelic medicine treatment and research company. He is a member of the Expert Committee of the Medical Cannabis Clinicians Society (MCCS) in the United Kingdom and sits on the Advisory Councils for Cannabis Patient Advocacy & Support Services (CPASS) and MedCan. SLI In the last 12 months, Dr. Irwin has received honoraria for authoring a chapter for the Canadian Pharmacy Association (CPhA) and for doing an online lecture for NeuroDiem. She also receives compensation for scientific consulting (Impel NeuroPharma Inc, Biohaven Pharmaceuticals and Lundbeck A/S) and has had research support from the Duke Clinical Research Institute. MC has been granted the 2022 Research Manitoba-George & Fay Yee Centre for Healthcare Innovation in Health Research PhD Studentship Award. RB, BS, TL, ZA, MCG, BID, GEB,KAB, VWLT, DP, AGW, ES, EP, ARM, SM, ZZ, SB, SG, JA, TFO, and GAF have no potential conflict of interest to declare. ### Clinical Trial CAN-CHA trial is registered with ClinicalTrials.gov with a number of register [NCT05337033][1]. ### Funding Statement This work was supported by the Hospital for Sick Children Foundation () and the Canadian Institutes of Health Research () grant number N120-1028 as a team grant Dr Lauren Kelly is principal investigator for this grant. An investigational product for this trial has been purchased from MediPharm Labs. The funders did not and will not have a role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study was approved by the University of Manitoba Health Research Ethics Board (HS25503-B2022:037). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Deidentified research data will be made publicly available when the study is completed and published. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT05337033&atom=%2Fmedrxiv%2Fearly%2F2023%2F08%2F07%2F2023.08.04.23293647.atom